Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most heavily consumed pharmaceuticals due to their great efficacy to reduce fever, pain and inflammation but are frequently associated with GI side-effects such as peptic ulceration and bleeding. In this Phase I application we outline a number of critical studies which are required to develop a family of NSAID-phospholipid prodrugs which protect rats from the acute GI toxicity of NSAlDs while maintaining or enhancing their therapeutic activity. We propose to establish animal models of arthritis in which to directly compare both the chronic GI toxicity and therapeutic activity of NSAIDs- phospholipid prodrugs to that of unmodified NSAIDs. Biochemical studies are proposed to examine the inhibitor-effects of the NSAID test- formulations on the cyclooxygenase isoenzymes of the GI mucosae. We also propose to employ analytical techniques to examine the effects of phospholipid on both the shelf-life and biological half-life of NSAlDs. The above studies in Phase I are required as a prelude to the more extensive in vivo and in vitro studies in Phase II, and the initiation of clinical studies with the corporate partner in Phase III, to meet our long-term goals of developing a GI-safe and highly active NSAID- phospholipid prodrugs. PROPOSED COMMERCIAL APPLICATION: Peptic ulcer disease and gastrointestinal bleeding represent the major complication of individuals consuming NSAIDs for the relief of pain, fever and inflammation. The market for GI-safe NSAID with enhanced therapeutic activity, which appear to be characteristics of the NSAID-phospholipid prodrugs, would be enormous.